Electrode apparatus and method for the delivery of drugs and genes into tissue

ABSTRACT

An electrode assembly for an apparatus for trans-surface molecular includes a non-conductive carrier having a proximal surface, a distal surface, and a plurality of through holes from the proximal surface to the distal surface, a plurality of first electrodes disposed on the proximal surface, a first conductor disposed on at least a first portion of the distal surface and extending through at least a first portion of the plurality of through holes and connected to the first electrodes on the proximal surface, a plurality of second electrodes disposed on the proximal surface, and a second conductor disposed on at least a second portion of the distal surface and extending through at least a second portion of the plurality of through holes and connected to the second electrodes on the proximal surface, wherein the first electrodes and the second electrodes are configured and disposed in closely spaced relation on the proximal surface for engaging the tissue surface and applying an electric field.

BACKGROUND OF THE INVENTION

[0001] The present invention relates generally to electroporation fordrug and gene delivery and pertains more particularly to an electrodeassembly for an apparatus for and a method of trans-surface delivery ofgenes, drugs, and other molecules through tissue surfaces for boththerapeutic and cosmetic purposes.

[0002] The medical community has in recent years been investigatingelectroporation as a method of trans-surface delivery of drugs, genessuch as DNA, portions of DNA, chemical agents, or other moleculeswithout physical penetration or invasion of the tissue surface. Thismethod can be used for the application of molecules for the therapeutictreatment of cancer or for cosmetic treatment of skin blemishes andabnormalities such as wrinkles and age spots. It can also be used forgene therapy. This method involves the electroporation of the tissuesurface through the application of an electrical field by means ofelectrodes on the tissue surface. Electroporation can make tissuepermeable to enable the molecules to pass through the tissue surface andmore readily enter the tissue. Electroporation can also make cell tissuepermeable to enable the molecules to enter preselected cells in thetissue without damaging them.

[0003] The molecules to be introduced into the cells are placed in closeproximity to the cells, either in the interstitial tissue surroundingthe cells or in a fluid medium containing the cells. The field isapplied at a predetermined strength and duration in order to make thewalls of the tissue surface transiently permeable to permit themolecules to pass through the tissue surface into the underlying tissue.

[0004] The voltage that must be applied to induce electroporation isproportional to the distance between the electrodes. When the spacebetween the electrodes is too great, the generated electric fieldpenetrates deep into the tissue where it causes unpleasant nerve andmuscle reaction. The applicants have discovered electrode arrays andconfigurations that maximize the field strength and reduce theunpleasant nerve and muscle reaction.

[0005] Electroporation can be carried out by a sophisticatedelectroporation system having programmable power sequence and durationprogrammed in. For example, a suitable system is disclosed in U.S. Pat.No. 5,869,326 issued Feb. 9, 1999 entitled ELECTROPORATION EMPLOYINGUSER-CONFIGURED PULSING SCHEME, which is incorporated herein byreference as though fully set forth. Broadly, that invention concerns anelectroporation apparatus for and method of generating and applying anelectric field according to a user-specified pulsing scheme. One exampleof such a pulsing scheme includes a low voltage pulse of a firstduration, immediately followed by a high voltage pulse of a secondduration, and immediately followed by a low voltage pulse of a thirdduration. The low voltage field acts to accumulate molecules at thetissue surface, the appropriately high voltage field acts to create anopening in the tissue surface, and the final low voltage field acts tomove the molecules through the tissue surface.

[0006] While electroporation provides new pathways through the tissuesurface for passages of molecules, it does not provide a needed drivingforce to those molecules to move them through the tissue surface orthrough the tissue to the cell site. As a result, it is desirable tocombine electroporation with techniques for providing a driving force.Iontophoresis alone, wherein low voltage is applied between widelyspaced electrodes for a long period of time, can transport chargedmolecules through existing pathways such as hair follicles and sweatglands. However, the volumes of molecules transported for a unit of timeis very small, and insufficient for many applications. Combiningelectroporation and iontophoresis can increase the amount transportedinitially while the created pathways are open. The paths created by theelectroporation stay open for a only short period of time and thenclose.

[0007] One example of a surface for the trans-surface delivery ofmolecules is the skin or the stratum corneum (SC). The SC consists of athin layer of dead cells with a high electrical resistance whichpresents a major obstacle to the administration of drugs and genestransdermally. However, this layer can be perforated by theadministration of short high voltage pulses, which create a dielectricbreakdown of the SC forming pores which can allow the passage ofmolecules.

[0008] There is a need for improved electrodes that maximize areas ofdesired field strength for tissue surfaces to which to applyelectroporation which surfaces vary by their size, shape, location,porosity, and accessability, among others. It is desirable that anelectrode assembly for an apparatus for and a method of trans-surfacemolecular delivery be available to efficiently accommodate a widevariety of these tissue surfaces.

SUMMARY AND OBJECTS OF THE INVENTION

[0009] It is the primary object of the present invention to provide animproved electrode assembly for an apparatus for and a method oftrans-surface molecular delivery which maximize areas of desired fieldstrength for tissue surfaces to which to apply electroporation.

[0010] In accordance with the primary aspect of the present invention,electrodes configured to apply to tissue surface are configured tominimize the conductive areas and areas of low field strength whilemaximizing the areas of desired field strength.

[0011] In accordance with the method molecules are brought into physicalcontact with the tissue surface, an electrode is contacted with thetissue surface, and an electric field is applied to the tissue surfaceby means of the electrode. This forms pores in the tissue surface. Thena driving force is applied to the tissue surface forcing the moleculesthrough the tissue surface into the underlying tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The above and other objects and advantages of the presentinvention will be appreciated from the following specification when readin conjunction with the accompanying drawings wherein:

[0013]FIG. 1 is a schematic diagram showing a combined electroporationand iontophoresis apparatus;

[0014]FIG. 2 is schematic diagram showing a n alternate embodiment of acombined electroporation and iontophoresis apparatus;

[0015]FIG. 3 is a plan view of a top or distal side of an electrodeassembly according to the present invention;

[0016]FIG. 4 is a plan view of a face or proximal side of an electrodeassembly according to the present invention;

[0017]FIG. 5 is an enlarged broken cross-sectional view of an electrodeassembly according to the present invention taken through the line 5-5of FIG. 4;

[0018]FIG. 6 is a view of a face or proximal side of an alternateembodiment of an electrode assembly according to the present invention;

[0019]FIG. 7 is a partial top view of a second electrode assemblyaccording to the present invention;

[0020]FIG. 8 is an enlarged broken cross-sectional view taken throughthe line 8-8 of FIG. 7 and

[0021]FIG. 9 is side elevation section view a combined electrode andreservoir embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention was devised to provide an improvedelectrode assembly for an apparatus for and a method of trans-surfacemolecular delivery that can accommodate a wide variety of tissuesurfaces that vary by their size, shape, location, porosity, andaccessability, among others. One example of a surface for thetrans-surface delivery of molecules is the skin or the stratum corneum(SC). The SC consists of a thin layer of dead cells with a highelectrical resistance which presents a major obstacle to theadministration of drugs and genes transdermally. However, this layer canbe perforated by the administration of short high voltage pulses, whichcreate a dielectric breakdown of the SC forming pores which can allowthe passage of molecules.

[0023] Iontophoresis alone, wherein low voltage is applied betweenwidely spaced electrodes for a long period of time, can transportcharged molecules through existing pathways such as hair follicles andsweat glands. However, the volumes of molecules transported for a unitof time is very small, and insufficient for many applications. As aresult, it is desirable to combine electroporation with techniques forproviding a driving force such as pressure, ultrasound,electroincorporation, and iontophoresis. First, pressure can be appliedmechanically by pressing on the electrode assembly with any suitablemeans for applying a reasonably uniform pressure over the desired area.Second, ultrasound can be applied by an ultrasound source. Third,electroincorporation can be applied to transport molecules through thetissue surface into the tissue. Fourth, iontophoresis can be applied asthe driving force.

[0024] A combination of electroporation and iontophoresis can be carriedout by a sophisticated combination system having two electrodeassemblies and two power supplies. For example, a suitable system isdisclosed in U.S. Pat. No. 6,009,345 issued Dec. 28, 1999, entitledMETHOD AND APPARATUS FOR A COMBINATION OF ELECTROPORATION ANDIONTOPHORESIS FOR THE DELIVERY OF DRUGS AND GENES, which is incorporatedherein by reference as though fully set forth. Broadly, one example ofthe apparatus disclosed in the above referenced patent and for which theelectrodes of the invention is shown here in FIG. 1.

[0025] Turning first to FIG. 1, a schematic diagram of a combinedelectroporation and iontophoresis apparatus 10 is shown. The apparatus10 includes an electroporation power supply 12, a first electrodeassembly 14, an iontophoresis power supply 16, and a second electrodeassembly 18 all of which are connected together by a network of switches(20, 22, 24, 26, 28, 30, 32, and 34) and conductors as shown. In oneembodiment, the first and second electrode assemblies 14, 18 eachinclude a first and a second electrode (not shown) which are in closelyspaced relation to each other. In another embodiment one electrodeassembly includes a first and second electrode and the other includes asingle electrode. It is contemplated that the electrode assemblies willbe in the form of a patch which may be worn for a period of time andpowered by a small battery pack.

[0026] In operation, electroporation and iontophoresis of the tissuesurface are performed sequentially. During electroporation, theelectroporation power supply 12 is connected to the first electrodeassembly 14 and the second electrode assembly 18 by closing switches 20,22, 24, and 26 while switches 28, 30, 32, and 34 are held open. Duringiontophoresis, the iontophoresis power supply 16 is connected to thefirst electrode assembly 14 and the second electrode assembly 18 byclosing switches 28, 30, 32, and 34 while switches 20, 22, 24, and 26are held open.

[0027] Alternatively, the second electrode assembly 18 could includeonly one electrode (not shown). In such an apparatus 10, switches 22 and26 would remain permanently open and switch 30 would remain permanentlyclosed. During electroporation, the electroporation power supply 12 isconnected to the first electrode assembly 14 by closing switches 20 and24 while switches 28, 32, and 34 are held open. During iontophoresis,the iontophoresis power supply 16 is connected to the first electrodeassembly 14 and the second electrode assembly 18 by closing switches 28,32, and 34 while switches 20 and 24 are held open. In this instance onlythe first electrode assembly 14 participates in the electroporation andboth participate in iontophoresis.

[0028] In one embodiment of the apparatus 10, the first and secondelectrode assemblies 14, 18 are each a special patch that is applied tospaced areas of the tissue surface. A solution containing the drugs orgenes to be introduced can be contained in the patch which also includesthe electrode structure to create the electric field forelectroporation. The electrode structure can be inside or on a surfaceof the patch and the patch would preferably contain a reservoir. Theelectrode structure is connected to two conductors outside of the patchso that the electroporation and iontophoresis power supplies 12, 16 canbe connected momentarily to these outside conductors to provide avoltage pulse. The patch is preferably provided with an adhesive borderto adhere it to the tissue surface. The tissue engaging area of thepatch is also preferably provided with a protective cover which can bepeeled off before adhering the patch to the tissue surface. This wouldalso allow fluid carrying drugs or genes to pass through openings in thepatch to the tissue surface.

[0029] When iontophoresis is used as the driving force, anelectrophoresis electrode is preferably separate from theelectroporation electrodes and may also be part of the patch andpositioned above the electroporation electrodes. The iontophoresisreturn electrode may also be remote from the patch electrode assembly ormay surround it. An electroporation pulse is first applied to theappropriate electrodes to open pores in the tissue surface. Aniontophoresis current is then applied between the appropriate electrodesto draw the drugs or genes through the pores.

[0030] Turning now to FIG. 2, a schematic diagram of a second oralternate embodiment of a combined electroporation and iontophoresisapparatus 40 is shown. The apparatus 40 includes an electroporationpower supply 12, a first electrode assembly 14, an iontophoresis powersupply 16, and a second electrode assembly 18 all of which are connectedtogether by a network of diodes (42, 44, 46, 48, 50, 52, and 54) andconductors as shown. The first and second electrode assemblies 14, 18each include a first and a second electrode (not shown) which are inclosely spaced relation to each other.

[0031] As in the prior embodiment discussed above, in operation,electroporation and iontophoresis of the tissue surface are performedsequentially. Unlike the prior embodiment, no switches are involvedhere. During electroporation, the electroporation power supply 12 isenergized and the iontophoresis power supply 16 is off. Duringiontophoresis, the iontophoresis power supply 16 is energized and theelectroporation power supply 12 is off. Otherwise, the apparatus of FIG.2 can be used in the same manner as the apparatus of FIG. This includesthe use of the subsequently described electrode assemblies describedwith respect to FIGS. 3, 4, and 5 below.

[0032] Turning now to FIG. 3, a view of a distal or back side of anelectrode assembly 60 according to a preferred embodiment of the presentinvention is shown. The electrode assembly 60 could be substituted foreither or both of the first and second electrode assemblies 14, 18 shownin FIG. 1. The electrode assembly 60 includes a non-conductive carrier62 which has a plurality of through holes 64 which run from the distalside to a proximal side (see FIG. 4). Disposed on the distal side is afirst conductor 66. The first conductor 66 extends through a firstportion 68 of the plurality of through holes 64 and onto the proximalside of the carrier and connect to a first plurality of electrodes.

[0033] A first lead or conductor 70 is coupled to the first conductor 86for connecting to a power supply. Also disposed on the distal side is asecond conductor 72. The second conductor 72 extends through a secondportion 74 of the plurality of through holes 64 and onto the proximalside and connect to a second plurality of electrodes. A second lead orconductor 76 is coupled to the second conductor 72 for connecting to apower supply. Optionally, an insulating barrier (not shown) may bedisposed on the distal side between the first conductor 66 and thesecond conductor 72.

[0034] Turning now to FIG. 4, a view of a proximal or front side of anelectrode assembly 60 according to a preferred embodiment of the presentinvention is shown. The proximal side is the side of the electrodeassembly 60 that would normally be placed near or against the tissuesurface (not shown) that is to be the subject of electroporation.Corresponding to the distal side (see FIG. 4), the proximal side has theplurality of through holes 64. The first conductor 66 extends throughthe first portion 68 of the plurality of through holes 64 from thedistal side and connect to the first plurality of electrodes 78. Thesecond conductor 72 extends through the second portion 74 of theplurality of through holes 64 from the distal side and connect to thesecond plurality of electrodes 80. Close inspection will reveal that thefirst electrode 66 and the second electrode 72 alternate in both thevertical and horizontal directions. Each electrode in the inner rows aresurrounded by four other electrodes of opposite polarity. The preferredshape of the electrodes shown in this embodiment is that of a square.This construction provides an array of electrodes configured to providea lot of edge area maximizing the edge effect. The area between theedges of the adjacent electrodes will be exposed to the desired fieldstrength.

[0035] The electrodes are separated by an insulation structure forming agrid structure surrounding each electrode and extending above or beyondthe surfaces thereof. This

tion forces the electrical field to penetrate the tissue surface ratherthan conduct along

ssue surface. This arrangement is particularly desirable where thetissue surface is

Optionally, an insulating barrier (not shown) may be disposed on theproximal side

en the first conductor 66 and the second conductor 72. Where the tissuesurface is to be

e insulation barrier may preferably be slightly below the electrodesurface to provide

area contact of the electrode surface with the tissue surface.

[0036] Turning now to FIG. 5, an enlarged broken cross-sectional view ofan electrode

bly 60 according to a second preferred embodiment of the presentinvention taken

h the line 5-5 of FIG. 4 is shown. Of particular interest in this viewis that one can see

e first conductor 66 extends through the first portion 68 of theplurality of through

4 and onto the proximal side. Further, one can see that the secondconductor 72

s through the second portion 74 of the plurality of through holes 64 andonto the

al side.

[0037] The illustrated embodiment of the electrode assembly 60 shown inFIGS. 3, 4, and 5 is

for illustration purposes. The final configuration will depend on theparticular

tion. As a result, the overall size, shape, and thickness may vary. Thesize, shape,

r, and location of the plurality of through holes 64 may vary. Theshape, thickness,

ation of the first electrode 78 and the second electrode 80 may vary.

[0038] In the preferred embodiment, the electrode assembly 60 ismanufactured using the

chniques used to create printed circuit boards. The carrier 62 is a thinflexible film

llows the electrode assembly 60 to be contoured to the tissue surfacewhich generally has an irregular shape. In one embodiment, the pluralityof through holes 64 are provided in part so that drugs and genes can besupplied from a reservoir (not shown) on the distal side and passthrough the plurality of through holes 64 to the tissue surface. Thefirst electrode 78 and the second electrode 80 are closely spaced so asto limit the penetration of the field to a shallow layer of the tissueand to maximize the edge effect. In the preferred embodiment, theelectrode assembly 60 is manufactured using the same techniques used tocreate printed circuit boards. The carrier 62 is a thin flexible filmwhich allows the electrode assembly 640 to be contoured to the tissuesurface which generally has an irregular shape. In one embodiment, theplurality of through holes 64 are provided in part so that drugs andgenes can be supplied from a reservoir (not shown) on the distal sideand pass through the plurality of through holes 64 to the tissuesurface. The insulating barrier 82 is a solder mask which reduces theflow of current directly between the first electrode 78 and the secondelectrode 80 across the tissue surface. However, the first electrode 46and the second electrode 54 are closely spaced so as to limit thepenetration of the field to a shallow layer of the tissue.

[0039] Turning now to FIG. 6, a view of a proximal or front side of analternate embodiment of an electrode assembly 86 according to anembodiment of the present invention is shown. The proximal side is theside of the electrode assembly 86 that would normally be placed near oragainst the tissue surface (not shown) that is to be the subject ofelectroporation. The electrode assembly comprises an insulating carrier88 of a thin flexible material on which is mounted a plurality ofelectrodes. An array of electrode units 90 are positioned in rowsthroughout the face of the carrier. Each electrode unit for the purposesof this description comprises a pair of electrodes positioned to to beconnected in opposite polarity and act in opposition to one another. Theelectrode units each comprise a first or center electrode 92 of acircular configuration, each surrounded by an electrode 94 of a ring ordoughnut configuration. These are configured to minimize the conductiveareas and areas of low field strength while maximizing the areas ofdesired high field strength.

[0040] The goal of the electrode configuration is to minimize theconductive areas and the areas of low field strength while maximizingthe areas of desired field strength. E.g., the area between the centerelectrodes and the ring electrodes will be exposed to the desired fieldstrength, whereas only parts of the area between doughnuts will beexposed to the desired field strength. The minimal area that can becovered by conductive materials is a function of the applied voltage,the specific conductivity of the conductive material, the cross-sectionof the conductive material and the conductivity of the material (e.g.,skin) with which the electrode is intended to be in contact with.Optimization of the electrode design will be based on theseconsiderations. Another consideration is the flatness of the electrodearray. If dry skin is to be electroporated, it appears advantageous tohave the surface of the conductive material raised by 0.1 to a few mmabove the surface of the non-conductive surfaces. If wet skin or the wetsurface of another organ is intended to be electroporated, the oppositeseems advantageous, i.e., the non-conductive surfaces should be raisedrelative to the conductive surfaces. In the first case, the raisedconductive material will ensure good contact with the dry surface to beelectroporated (e.g., dry skin). In the latter case the raisedinsulating material will help to minimize leakage current betweenelectrodes via the liquid on the surface to be electroporated.

[0041] The connection of conductors to the electrodes may be carried outwith a structure of conductors substantially like that of FIG. 3. In oneembodiment, the electrodes are connected by a series of conductors asillustrated in FIG. 7. FIG. 7 is a partial view of the distal or backside of the electrode assembly of FIG. 6 showing an exempleryarrangement of conductors to the electrodes on the face of the electrodeassembly. A first conductor 96 extends along one end and a side of thecarrier and connects via through holes at 100, 102, 104 and 106 to thering electrodes 94 of the end row of electrode units. A second conductorextends across the carrier and connects via open through holes 110, 112,114 and 116 to the center electrodes 92 of the first row of electrodeunits. The second conductor also connects via through holes 118, 120,122, 124 and 126 to the ring electrodes of the next row of electrodeunits. It will be seen that the center electrodes of the units will beof different polarity than the ring electrode of that unit. Also thecenter electrode of one row will have the same polarity as the ringelectrode of an adjacent row of electrode units. It will be appreciatedthat other connection arrangements may be made to achieve the object ofthe invention.

[0042] The electrode assemblies herein described are designed to beincorporated into a patch as illustrated in FIG. 9 to be applied to thetissue surface such as by an adhesive and powered such as by a batterypack. An exemplary patch designated generally at 130 comprises a carrier132 on which is mounted electrodes 134 with conductors as described inprevious embodiments above. A bladder 136 forms a reservoir 138 abovethe electrode assembly and contains a fluid medium to carry molecules tobe delivered to the tissue. A driving force F is applied to the fluid inthe reservoir to force the molecules from the reservoir into the tissue.If the driving force is iontophoresis, an iontophoresis electrode 140 ispositioned above the electrodes 134 and a return iontophoresis electrodecan be remote from the patch or may surround it.

[0043] Alternate force applying means 142 can be an ultrasonictransducer or other suitable means for forcing the fluid from thereservoir into the tissue.

[0044] The techniques of electroincorporation may also be used with theherein detailed system and electrodes for the delivery of moleculesacross tissue surface. This technique is more fully disclosed in U.S.Pat. Nos. 5,462,520 and 5,464,386, which are incorporated herein byreference as though fully set forth.

[0045] While the invention has been illustrated and described by meansof specific embodiments, it is to be understood that numerous changesand modifications may be made therein without departing from the spiritand scope of the invention as defined in the appended claims.

What is claimed is:
 1. An electrode assembly for electroporation of atissue surface, comprising: a non-conductive carrier having a proximalsurface, a distal surface, and a plurality of through holes from theproximal surface to the distal surface; a plurality of first electrodesdisposed on the proximal surface; a first conductor disposed on at leasta first portion of the distal surface and extending through at least afirst portion of the plurality of through holes and connected to thefirst electrodes on the proximal surface; a plurality of secondelectrodes disposed on the proximal surface; and a second conductordisposed on at least a second portion of the distal surface andextending through at least a second portion of the plurality of throughholes and connected to the second electrodes on the proximal surface;wherein the first electrodes are in closely spaced relation with thesecond electrodes on the proximal surface for engaging the tissuesurface and applying an electric field.
 2. The electrode assemblyaccording to claim 1 wherein the carrier comprises a thin flexible film.3. The electrode assembly according to claim 2 wherein each electrode issurrounded by at least one electrode of an opposite polarity.
 4. Theelectrode assembly according to claim 3 wherein one of said electrodesis a center electrode and another electrode is a ring electrodesurrounding said one electrode.
 5. The electrode assembly according toclaim 4 wherein said electrodes are disposed in a grid pattern.
 6. Theelectrode assembly according to claim 3 wherein said electrodes aresubstantially square in configuration wherein said electrodes arecircular in configuration.
 7. The electrode assembly according to claim6 wherein said electrodes are disposed in a grid pattern.
 8. Theelectrode assembly according to claim 3 wherein said electrodes areconcentrically disposed of alternate polarity.
 9. The electrode assemblyaccording to claim 8 wherein said electrodes are disposed in multiplealternate rows of different numbers.
 10. The electrode assemblyaccording to claim 1 comprising a fluid reservoir on said distal surfaceof said non-conductive carrier in communication with said plurality ofthrough holes for conveying fluid to the surface of said electrodes. 11.The electrode assembly according to claim 1 further comprising aninsulating barrier that is disposed on at least a third portion of theproximal surface of the carrier between the first electrodes and thesecond electrodes and projecting above the surface of the electrodes.12. An apparatus for trans-surface molecular delivery, comprising: afirst electrode assembly, comprising: a non-conductive carrier having aproximal surface, a distal surface, and a plurality of through holesfrom the proximal surface to the distal surface; a plurality of firstelectrodes disposed on at least a first portion of the proximal surface;a first conductor disposed on said distal surface and extending throughat least a first portion of the plurality of through holes and connectedto the plurality of first electrodes; and a plurality of secondelectrodes disposed on at least a second portion of the of the proximalsurface; a second conductor disposed on said distal surface andextending through at least a second portion of the plurality of throughholes and connected to the plurality of second electrodes; wherein thefirst electrodes are in closely spaced relation with the secondelectrodes on the proximal surface for engaging the tissue surface andapplying an electric field; a first power supply connected to the firstelectrode assembly for applying a pulsed electric field of sufficientamplitude to induce pores in the tissue surface; and means for drivingmolecules through pores in the tissue surface.
 13. The apparatusaccording to claim 12 wherein means for driving comprises: a secondelectrode assembly spaced from the first electrode assembly andcomprising at least one of an anode and a cathode; and a second powersupply connected to the first electrode assembly and the secondelectrode assembly for applying a low voltage continuous electric fieldof a preselected polarity and sufficient amplitude to induce migrationof molecules through pores in the tissue surface.
 14. The apparatusaccording to claim 12 wherein means for driving comprises a pressuresource in communication with the tissue surface via the plurality ofthrough holes in the carrier of the first electrode assembly forapplying pressure of a sufficient amplitude and duration to inducemigration of molecules through pores in the tissue surface.
 15. Theapparatus according to claim 12 wherein means for driving comprises anultrasound source for applying ultrasound of a sufficient amplitude andduration to induce migration of molecules through pores in the tissuesurface.
 16. The apparatus according to claim 12 wherein means fordriving comprises means for electroincorporation of molecules forapplying electroincorporation of a sufficient amplitude and duration toinduce migration of particles containing molecules through pores in thetissue surface.
 17. The apparatus according to claim 12, wherein saidfirst power supply and said second power supply comprising: anelectroporation power supply having a first contact and a second contactwherein a pulsed electric field of sufficient amplitude to induce poresin the tissue surface is applied; an iontophoresis power supply having afirst contact and a second contact wherein a low voltage continuouselectric field of a preselected polarity and sufficient amplitude toinduce migration of molecules through pores in the tissue surface isapplied; a first electrode assembly having a first contact and a secondcontact; a second electrode assembly having a first contact and a secondcontact; a first diode having an input connected to the first contact ofthe electroporation power supply and an output connected to the firstcontact of the first electrode assembly; a second diode having an inputconnected to the first contact of the electroporation power supply andan output connected to the first contact of the second electrodeassembly; a third diode having an input connected to the second contactof the first electrode assembly and an output connected to the secondcontact of the electroporation power supply; a fourth diode having aninput connected to the second contact of the second electrode assemblyand an output connected to the second contact of the electroporationpower supply; a fifth diode having an input connected to the firstcontact of the iontophoresis power supply and an output connected to thefirst contact of the first electrode assembly; a sixth diode having aninput connected to the first contact of the iontophoresis power supplyand an output connected to the second contact of the first electrodeassembly; and a seventh diode having an input connected to the secondcontact of the second electrode assembly and an output connected to thesecond contact of the iontophoresis power supply.
 18. A method oftrans-surface molecular delivery, comprising: providing a firstelectrode assembly, comprising: a non-conductive carrier having aproximal surface, a distal surface, and a plurality of through holesfrom the proximal surface to the distal surface; a first electrodedisposed on at least a portion of the distal surface and extendingthrough at least a portion of the plurality of through holes and onto atleast a portion of the proximal surface; and a second electrode disposedon at least a portion of the proximal surface and in closely spacedrelation with the first electrode; engaging a tissue surface with thefirst electrode assembly; providing a first power supply connected tothe first electrode assembly; applying a pulsed electric field via thefirst electrode assembly of sufficient amplitude to induce pores in thetissue surface; providing means for driving molecules through pores inthe tissue surface; and applying means for driving to induce migrationof molecules through pores in the tissue surface.
 19. The methodaccording to claim 18 wherein the step of providing means for drivingcomprises the steps of: providing a second electrode assembly spacedfrom the first electrode assembly and comprising at least one of ananode and a cathode; and providing a second power supply connected tothe first electrode assembly and the second electrode assembly, andwherein the step of applying means for driving comprises the step ofapplying a low voltage continuous electric field of a preselectedpolarity and sufficient amplitude to induce migration of moleculesthrough pores in the tissue surface.
 20. The method according to claim18 wherein the step of providing means for driving comprises the step ofproviding a pressure source in communication with the tissue surface viathe plurality of through holes in the carrier of the first electrodeassembly and wherein the step of applying means for driving comprisesthe step of applying pressure to the first electrode assembly of asufficient amplitude and duration to induce migration of moleculesthrough pores in the tissue surface.
 21. The method according to claim18 wherein the step of providing means for driving comprises the step ofproviding an ultrasound source and wherein the step of applying meansfor driving comprises the step of applying ultrasound of a sufficientamplitude and duration to induce migration of molecules through pores inthe tissue surface.
 22. The method according to claim 18 wherein thestep of providing means for driving comprises the step of providingmeans for electroincorporation of molecules and wherein the step ofapplying means for driving comprises the step of applying means forelectroincorporation of a sufficient amplitude and duration to inducemigration of particles containing molecules through pores in the tissuesurface.
 23. An apparatus for trans-surface molecular delivery,comprising: an electroporation power supply having a first contact and asecond contact wherein a pulsed electric field of sufficient amplitudeto induce pores in the tissue surface is applied; an iontophoresis powersupply having a first contact and a second contact wherein a low voltagecontinuous electric field of a preselected polarity and sufficientamplitude to induce migration of molecules through pores in the tissuesurface is applied; a first electrode assembly having a first contactand a second contact; a second electrode assembly having a first contactand a second contact; a first diode having an input connected to thefirst contact of the electroporation power supply and an outputconnected to the first contact of the first electrode assembly; a seconddiode having an input connected to the first contact of theelectroporation power supply and an output connected to the firstcontact of the second electrode assembly; a third diode having an inputconnected to the second contact of the first electrode assembly and anoutput connected to the second contact of the electroporation powersupply; a fourth diode having an input connected to the second contactof the second electrode assembly and an output connected to the secondcontact of the electroporation power supply; a fifth diode having aninput connected to the first contact of the iontophoresis power supplyand an output connected to the first contact of the first electrodeassembly; a sixth diode having an input connected to the first contactof the iontophoresis power supply and an output connected to the secondcontact of the first electrode assembly; and a seventh diode having aninput connected to the second contact of the second electrode assemblyand an output connected to the second contact of the iontophoresis powersupply.